Deregulated Profile of lncRNA Molecules Linked to ALS, Study Shows

From ALS News Today by Alice Melao – The amount of RNA molecules present in the blood and central nervous system of amyotrophic lateral sclerosis (ALS) patients seems to play a role in the onset and development of the disease, a study published in the journal Scientific Reportsshowed.

A better understanding of the involvement of RNA molecules on ALS may improve understanding about the disease and pave the way for better treatment and diagnosis options.

Several studies have demonstrated that RNA molecules and their metabolism play a critical role in many diseases, including ALS. Small RNA molecules have been shown to be important contributors not only for disease progression, but they also have been proposed as diagnostic biomarkers, and potential treatment tools for ALS.

The team analyzed the levels of several types of RNA molecules in immune cells collected from the blood of 30 healthy volunteers and 30 individuals with sporadicALS. In addition, they also analyzed samples collected from seven ALS patients who were carriers of mutations in genes linked to familial ALS (FUS, SOD1, or TARDBP).

This analysis revealed a total of 293 long non-coding RNAs (lncRNAs) that were present in different amounts in sporadic ALS patients compared to “control” participants, of which 183 were increased and 110 were decreased. In patients with inherited ALS, researchers found fewer deregulated lncRNAs. Only 21, 15, and two lncRNAs were identified in FUS, TARDBP, and SOD1 mutated samples, respectively.

To validate these findings, the team selected the 10 most deferentially altered lncRNAs and evaluated their levels in spinal cord samples collected postmortem from ALS patients and healthy individuals.

In this new analysis the selected RNA molecules continued to show a significant difference between ALS patients and controls, with the same deregulation pattern as seen in the blood samples. This finding suggests that lncRNAs are important not only in ALS-related cellular processes in the periphery, but also in the central nervous system.

When researchers screened for coding RNA sequences, so-called mRNAs (the molecules transcribed from DNA that will serve as templates for proteins), they found that 87 were expressed differently in sporadic ALS patients. In mutated ALS, the analysis revealed a different mRNA profile between patient groups, with 122 altered mRNAs detected in FUS group, 30 in TARDBP, and 18 in SOD1 patients.

In panel (A), differentially expressed mRNAs are shown, while in panel (B) differentially expressed lncRNAs are shown. All comparisons are given between the disease state and the control samples. We considered as differentially expressed only genes showing |log2(disease sample/healthy donor)| ≥ 1 and a False Discovery Rate ≤ 0.1.

Evaluation of the cellular role of these deregulated mRNAs showed they were associated mainly with gene levels regulation, immunity, and cell death regulation.

“Our data brought the light on the importance of RNA regulation in central and peripheral system, offering numerous starting points for new investigations about pathogenic mechanism involved in ALS disease,” the researchers stated.

Overall, these findings showed that RNA molecules, in particular lncRNAs, are important regulators of ALS-related cellular mechanisms. Additional studies are still warranted to further understand the role of these molecules in ALS development and progression.

“Future studies will be focused on the correlation between the progression of the disease and the RNAs profile,” they said.